Composition for preventing the occurrence of cardiovascular event in multiple risk patient

ABSTRACT

Disclosed is a composition which is useful for preventing the occurrence of a cardiovascular event, particularly a composition which is expected to show a prophylactic effect on a cardiovascular event occurring in a hypercholesterolemia patient despite providing the patient with a treatment with HMG-CoA RI or a cardiovascular event occurring in a multiple risk patient.

TECHNICAL FIELD

This invention relates to a composition for preventing occurrence ofcardiovascular events (primary prevention) in multiple risk patients,the composition containing at least ethyl icosapentate (hereinafterabbreviated as EPA-E).

BACKGROUND ART

Westernization of diet has resulted in the increase of patientssuffering from lifestyle-related diseases such as diabetes,hyperlipidemia, and hypertension. Some of these diseases finally lead toarteriosclerotic diseases such as myocardial infarction, anginapectoris, and cerebral infarction. Treatment of the lifestyle-relateddiseases is based on the improvement of lifestyle, and morespecifically, on the alimentary therapy and kinesitherapy. However, suchimprovement of the dietary life or the lack of exercise is oftendifficult in the patients suffering from the “lifestyle-relateddiseases”, and they usually transfer to pharmacotherapy in order toprevent poor prognosis, for example, onset of myocardial infarction orcerebral infarction.

An exemplary compound having the action of improving suchlifestyle-related diseases is polyunsaturated fatty acid. Thepolyunsaturated fatty acid is defined as a fatty acid including two ormore carbon-carbon double bonds in one molecule, and the polyunsaturatedfatty acids are categorized by the position of the double bond into ω3fatty acid, ω6 fatty acid, and the like. The ω3 polyunsaturated fattyacids include α-linolenic acid, icosapentaenoic acid (EPA), anddocosahexaenoic acid (DHA), and the ω6 polyunsaturated fatty acidsinclude linoleic acid, γ-linolenic acid, and arachidonic acid.Polyunsaturated fatty acids are derived from natural products, andexhibit various actions including antiarteriosclerotic action, plateletaggregation inhibitory action, hypolipidemic action, antiinflammatoryaction, antitumor action, and central action, and due to the highsafety, polyunsaturated fatty acids are incorporated in various kinds offood, or sold as a health food or drug.

Decrease in the death rate in the patients who have history of sufferingfrom myocardial infarction has been reported for the administration of amixture of ethyl ester of an ω-3 polyunsaturated fatty acid EPA (EPA-E)and ethyl ester of an ω-3 polyunsaturated fatty acid DHA (DHA-E) for 3.5years (see Patent Document 1). However, the results disclosed in PatentDocument 1 relates to the secondary prevention, that is, prevention ofrecurrence, and the drug which is effective in the secondary preventionis not always effective in the primary prevention.

Based on the results of animal experiments and small scale clinicalobservations, many large scale clinical trials have been recentlyplanned and conducted for the purpose of confirming whether variousdrugs which are effective in improving the lifestyle-related diseasescan also prevent arteriosclerotic diseases in human. The results,however, have not necessarily been as intended, and the situation isstill severe for the prevention of the occurrence of cardiovascularevents in the case of patients suffering from a plurality of riskfactors.

High purity EPA-E is commercially available in the trade names ofEpadel™ and Epadel S™ (manufactured by Mochida Pharmaceutical Co., Ltd.)as therapeutic drugs for hyperlipidemia. There has been reported thatwhen such high purity EPA-E is orally administered at 600 mg peradministration and 3 times a day immediately after meal (when TG isabnormal, the dose is increased to the level of 900 mg peradministration and 3 times a day), serum T-Cho concentration can bereduced by 3 to 6%, and serum TG can be reduced by 14 to 20% (seeNon-Patent Document 1). There has also been reported in The HeartFailure Society of America 2005 Annual Meeting that, based on suchaction, such high purity EPA-E was expected to have the effects ofimproving cardiovascular events in hyperlipidemia patients, and combineduse with HMG-CoA RI was effective in inhibiting cardiac events in alarge scale clinical trial. In this large scale clinical trial (JELIS,Japan EPA Lipid Intervention Study)), statistically significantsuppression of the cardiac events by the EPA-E was confirmed for thetotal of the primary prevention patients and secondary preventionpatients, and for the secondary prevention patients. On the other hand,in the analysis limited to the primary prevention patients, theincidence of the events was lower in the EPA-E group (the groupadministered with EPA-E in combination with HMG-CoA RI) compared to thecontrol group (the group administered with solely with HMG-CoA RI),while this difference was not statistically significant. This trial alsorevealed that after 5 years from the start of the trial, theLDL-cholesterol value reduced by 26% in both of the EPA-F group andcontrol group, that no significant difference was found between thesegroups, and that change of the HDL-cholesterol value was slight in bothgroups (see Non-Patent Document 2). This trial also revealed that thetotal cholesterol and the LDL-cholesterol decreased by 19% and 25%,respectively, in both of the EPA-E group and the control group, and thattriglyceride decreased by 9% (significant) and 4% in the EPA-E group andthe control group, respectively, while little change in HDL-C was notedin both of the EPA-E group and the control group (see Non-PatentDocument 3). There is so far no report that has analyzed prevention ofthe occurrence of the cardiovascular events in the case of patientshaving two or more risk factors.

Patent Document 1: WO 00/48592 (JP 2002-537252 A)

Non-Patent Document 1: Drug Interview Form “EPA preparation, Epadelcapsule 300”, revised in July, 2002 and February, 2004, version 21issued in December, 2004; pp. 21-22.

Non-Patent Document 2: Medical Tribune, issue of Nov. 17, 2005, Featurearticle 3, pp. 75-76.

Non-Patent Document 3: Lancet, vol. 369, pages 1090 to 1098 (2007).

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

In view of the situation that there is a serious problem that death fromthe cardiovascular disease is still a major cause of the death, and manycases of cardiovascular events are still impossible to prevent by theHMG-CoA RI therapy, an object of the present invention is to provide acomposition for preventing onset of the cardiovascular events.

Means to Solve the Problems

In order to solve the problems as described above, the inventors of thepresent invention made an extensive study on a therapy ofhypercholesterolemia patients and found that EPA-E has the effect ofpreventing occurrence of the cardiovascular events in patients sufferingfrom multiple risk factors, and in particular, the effect of preventingoccurrence of the cardiovascular events in male patients suffering frommultiple risk factors. The present invention has been completed on thebases of such finding. Accordingly, the present invention is directed tothe following:

(1) A composition for preventing occurrence of a cardiovascular event(primary prevention) in a hypercholesterolemia patient, the compositioncontaining at least EPA-E as its effective component, wherein thepatient also suffers from at least one risk factor selected from thegroup consisting of

(1) obesity,

(2) hypertension or prehypertension,

(3) diabetes, prediabetes, or abnormal glucose tolerance, and

(4) hypertriglyceridemia and/or low HDL cholesterolemia.

(2) A composition for preventing occurrence of a cardiovascular event ina hypercholesterolemia patient, the composition containing at leastEPA-E as its effective component, wherein the hypercholesterolemiapatient is a patient also suffering from two or more of the riskfactors.(3) A composition for preventing occurrence of a cardiovascular event ina hypercholesterolemia patient, the composition containing at leastEPA-E as its effective component, wherein the patient also suffers fromat least one of risk factors as defined by a body mass index (BMI) of atleast 25 for the obesity; by a systolic blood pressure (SBP) of at least140 mmHg or a diastolic blood pressure (DBP) of at least 90 mmHg for thehypertension or the prehypertension; by a fasting blood glucose (FBS) ofat least 126 mg/dL or a hemoglobin A1c (HbA1c) of at least 6.5% for thediabetes, the prediabetes, or the abnormal glucose tolerance; and bytriglyceride (TG) of at least 150 mg/dL and/or a HDL-C of less than 40mg/dL for the hypertriglyceridemia and/or the low HDL cholesterolemia.(4) The composition according to any one of (1) to (3) above, whereinthe content of the EPA-E is at least 96.5% by weight in relation to thetotal content of fatty acid and derivatives thereof.(5) The composition according to any one of (1) to (4) above, whereinthe EPA-E is orally administered at a dose of 1.8 g/day to 2.7 g/day.(6) The composition according to any one of (1) to (5) above, whereinthe composition is used in combination with HMG-CoA RI.(7) The composition according to any one of (1) to (6) above, whereinthe hypercholesterolemia patient is a male patient.(8) The composition according to any one of (1) to (7) above, whereinthe hypercholesterolemia patient is a patient also suffering fromhypertriglyceridemia and low HDL cholesterolemia.(9) A method for preventing occurrence of a cardiovascular event in ahypercholesterolemia patient by administering the patient with thecomposition according to any one of (1) to (8) above.(10) Use of the composition according to any one of (1) to (8) above forthe manufacture of an agent for preventing occurrence of acardiovascular event in a hypercholesterolemia patient.

MERITS OF THE INVENTION

The above-mentioned composition of the present invention containing atleast EPA-E as its effective component is effective in preventingoccurrence of cardiovascular events in hypercholesterolemia patients,and in particular, in preventing occurrence of cardiovascular events inhypercholesterolemia patients who have been treated with HMG-CoA RI butstill suffer from the risk of the cardiovascular events, or moreparticularly, in preventing occurrence of cardiovascular events inhypercholesterolemia patients also suffering from at least one riskfactor selected from the group consisting of

(1) obesity,

(2) hypertension or prehypertension,

(3) diabetes, prediabetes, or abnormal glucose tolerance, and

(4) hypertriglyceridemia and/or low HDL cholesterolemia.

The effect of the composition of the present invention will besynergistically improved by combined use with the HMG-CoA RI, and suchuse of the composition of the present invention with the HMG-CoA RI hasclinical utility since the effect of preventing the cardiovascular eventoccurrence is expected to be improved.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph prepared by plotting the incidence of thecardiovascular events in Y-axis and the time after the start of thetrial in X-axis for male patients having at least 2 risk factors.

FIG. 2 is a graph prepared by plotting the incidence of thecardiovascular event in Y-axis and the time after the start of the trialin X-axis for patients having the risk factors of a triglyceride (TG) ofat least 150 mg/dL and a HDL-C of less than 40 mg/dL.

BEST MODE FOR CARRYING OUT THE INVENTION

Next, the present invention is described in detail.

A first aspect of the present invention provides a composition forpreventing occurrence of a cardiovascular event (primary prevention) ina hypercholesterolemia patient, the composition containing at leastEPA-E as its effective component, wherein the patient also suffers fromat least one risk factor selected from the group consisting of

(1) obesity,

(2) hypertension or prehypertension,

(3) diabetes, prediabetes, or abnormal glucose tolerance, and

(4) hypertriglyceridemia and/or low HDL cholesterolemia. Alternatively,the first aspect of the present invention provides a composition forpreventing occurrence of a cardiovascular event (primary prevention) ina hypercholesterolemia patient, the composition containing at leastEPA-E and/or DHA-E as its effective component, wherein the patient alsosuffers from at least one risk factor selected from the group consistingof

(1) obesity,

(2) hypertension or prehypertension,

(3) diabetes, prediabetes, or abnormal glucose tolerance, and

(4) hypertriglyceridemia and/or low HDL cholesterolemia.

The prevention of the occurrence of the cardiovascular events includeall cases of primary prevention, and exemplary cases include preventionof cardiovascular death, fatal myocardial infarction, sudden cardiacdeath, nonfatal myocardial infarction, cardiovascular angioplasty, newoccurrence of rest angina and exercise-induced angina, anddestabilization of the angina. The composition of the present inventionmay be administered to any person who needs prevention of the occurrenceof the cardiovascular events, and typical such patients arehypercholesterolemia patients.

A second aspect of the present invention provides a composition forpreventing occurrence of a cardiovascular event in ahypercholesterolemia patient undergoing a HMG-CoA RI therapy, thecomposition containing at least EPA-E, wherein the patient also suffersfrom at least one risk factor selected from the group consisting of

(1) obesity,

(2) hypertension or prehypertension,

(3) diabetes, prediabetes, or abnormal glucose tolerance, and

(4) hypertriglyceridemia and/or low HDL cholesterolemia. Alternatively,the second aspect of the present invention provides a composition forpreventing occurrence of a cardiovascular event in ahypercholesterolemia patient undergoing a HMG-CoA RI therapy, thecomposition containing at least EPA-E and/or DHA-E, wherein the patientalso suffers from at least one risk factor selected from the groupconsisting of

(1) obesity,

(2) hypertension or prehypertension,

(3) diabetes, prediabetes, or abnormal glucose tolerance, and

(4) hypertriglyceridemia and/or low HDL cholesterolemia.

While HMG-CoA RI includes all those having inhibitory action for3-hydroxy-3-methylglutaryl coenzyme A reductase, the one used in thepresent invention is preferably a pharmaceutically administrableinhibitor which is preferably at least one member selected from thegroup consisting of pravastatin, simvastatin, lovastatin, fluvastatin,cerivastatin, atorvastatin, pitavastatin, rosuvastatin, and salts andderivatives thereof, and more preferably, pravastatin, lovastatin,simvastatin, fluvastatin, atorvastatin, pitavastatin, or rosuvastatin,and most preferably, pravastatin or simvastatin. All salts are includedas long as they are pharmaceutically administrable, and preferred aresodium and calcium salts such as pravastatin sodium, fluvastatin sodium,cerivastatin sodium, atorvastatin calcium, pitavastatin calcium, androsuvastatin calcium. In the present invention, “pravastatin”, forexample, also includes the pravastatin in the form of a salt unlessotherwise noted.

A third aspect of the present invention provides a composition forpreventing occurrence of a cardiovascular event in ahypercholesterolemia patient, the composition containing at least EPA-Eas its effective component, wherein the patient also suffers from atleast two risk factors selected from the group consisting of

(1) obesity,

(2) hypertension or prehypertension,

(3) diabetes, prediabetes, or abnormal glucose tolerance, and

(4) hypertriglyceridemia and/or low HDL cholesterolemia; namely;obesity, and hypertension or prehypertension; obesity, and diabetes,prediabetes, or abnormal glucose tolerance; obesity, andhypertriglyceridemia and/or low HDL cholesterolemia; hypertension orprehypertension, and diabetes, prediabetes or abnormal glucosetolerance; hypertension or prehypertension, and hypertriglyceridemiaand/or low HDL cholesterolemia; diabetes, prediabetes, or abnormalglucose tolerance, and hypertriglyceridemia and/or low HDLcholesterolemia; obesity, and hypertension or prehypertension, anddiabetes, prediabetes, or abnormal glucose tolerance; obesity, andhypertension or prehypertension, and hypertriglyceridemia and/or low HDLcholesterolemia; obesity, and diabetes, prediabetes, or abnormal glucosetolerance, and hypertriglyceridemia and/or low HDL cholesterolemia;hypertension or prehypertension, and diabetes, prediabetes, or abnormalglucose tolerance, and hypertriglyceridemia and/or low HDLcholesterolemia; obesity, and hypertension or prehypertension, anddiabetes, prediabetes, or abnormal glucose tolerance, andhypertriglyceridemia and/or low HDL cholesterolemia.

Alternatively, the third aspect of the present invention provides acomposition for preventing occurrence of a cardiovascular event in ahypercholesterolemia patient, the composition containing at least EPA-Eand/or DHA-E as its effective component, wherein the patient alsosuffers from at least two risk factors selected from the groupconsisting of

(1) obesity,

(2) hypertension or prehypertension,

(3) diabetes, prediabetes, or abnormal glucose tolerance, and

(4) hypertriglyceridemia and/or low HDL cholesterolemia.

A fourth aspect of the present invention provides a composition forpreventing occurrence of a cardiovascular event in ahypercholesterolemia patient, the composition containing at least EPA-Eas its effective component, wherein the patient also suffers from atleast one, and more preferably, at least two risk factors selected fromthe group consisting of

(1) obesity,

(2) hypertension or prehypertension,

(3) diabetes, prediabetes, or abnormal glucose tolerance, and

(4) hypertriglyceridemia and/or low HDL cholesterolemia. In this case,the hypercholesterolemia patient is preferably a male patient.Alternatively, the fourth aspect of the present invention provides acomposition for preventing occurrence of a cardiovascular event in ahypercholesterolemia patient, the composition containing at least EPA-Eand/or DHA-E as its effective component, wherein the patient alsosuffers from at least one, and more preferably, at least two riskfactors selected from the group consisting of

(1) obesity,

(2) hypertension or prehypertension,

(3) diabetes, prediabetes, or abnormal glucose tolerance, and

(4) hypertriglyceridemia and/or low HDL cholesterolemia. In this case,the hypercholesterolemia patient is preferably a male patient.

A fifth aspect of the present invention provides a composition forpreventing occurrence of a cardiovascular event in ahypercholesterolemia patient, the composition containing at least EPA-Eas its effective component, wherein the patient also suffers from riskfactors of hypertriglyceridemia and low HDL cholesterolemia, and morespecifically, hypertriglyceridemia and low HDL cholesterolemia with aserum triglyceride (TG) concentration of at least 150 mg/dl and a serumHDL-C concentration of less than 40 mg/dl, or serum TG/HDL-C ratio of atleast 3.75. In this case, the hypercholesterolemia patient is preferablya male patient. Alternatively, the fifth aspect of the present inventionprovides a composition for preventing occurrence of a cardiovascularevent in a hypercholesterolemia patient, the composition containing atleast EPA-E and/or DHA-E as its effective component, wherein the patientalso suffers from risk factors of hypertriglyceridemia and low HDLcholesterolemia, and more specifically, hypertriglyceridemia and low HDLcholesterolemia with a serum triglyceride (TG) concentration of at least150 mg/dl and a serum HDL-C concentration of less than 40 mg/dl, or aserum TG/HDL-C ratio of at least 3.75. In this case, thehypercholesterolemia patient is preferably a male patient.

A sixth aspect of the present invention provides a compositioncontaining at least EPA-E as its effective component, the compositionexhibiting an excellent effect of preventing occurrence of acardiovascular event in a patient suffering from multiple risk factorswho has been administered with this composition for at least 2 yearssince the start of the administration. Alternatively, the sixth aspectof the present invention provides a composition containing at leastEPA-E and/or DHA-E as its effective component, the compositionexhibiting an excellent effect of preventing recurrence of acardiovascular event in a patient suffering from multiple risk factorswho has been administered with this composition for at least 2 yearssince the start of the administration. The hypercholesterolemia patientis preferably a male patient.

A seventh aspect of the present invention provides a method forpreventing occurrence of a cardiovascular event in a patient sufferingfrom multiple risk factors by continuously administering the patientwith a composition containing at least EPA-E as its effective componentfor at least 2 years. Alternatively, the seventh aspect of the presentinvention provides a method for preventing occurrence of acardiovascular event in a patient suffering from multiple risk factorsby continuously administering the patient with a composition containingat least EPA-E and/or DHA-E as its effective component for at least 2years. The hypercholesterolemia patient is preferably a male patient.

An eighth aspect of the present invention provides a composition forpreventing occurrence of a cardiovascular event (primary prevention) ina dyslipidemia patient, the composition containing at least EPA-E as itseffective component, wherein the patient also suffers from at least onerisk factor selected from the group consisting of

(1) obesity,

(2) hypertension or prehypertension,

(3) diabetes, prediabetes, or abnormal glucose tolerance, and

(4) hypertriglyceridemia and/or low HDL cholesterolemia. Alternatively,the eighth aspect of the present invention provides a composition forpreventing occurrence of a cardiovascular event (primary prevention) ina dyslipidemia patient, the composition containing at least EPA-E and/orDHA-E as its effective component, wherein the patient also suffers fromat least one risk factor selected from the group consisting of

(1) obesity,

(2) hypertension or prehypertension,

(3) diabetes, prediabetes, or abnormal glucose tolerance, and

(4) hypertriglyceridemia and/or low HDL cholesterolemia.

A ninth aspect of the present invention provides a composition forpreventing occurrence of a cardiovascular event (primary prevention) ina hypercholesterolemia patient to be able to administered with HMG-CoARI, the composition containing at least EPA-E as its effectivecomponent, wherein the patient also suffers from at least one riskfactor selected from the group consisting of

(1) obesity,

(2) hypertension or prehypertension,

(3) diabetes, prediabetes, or abnormal glucose tolerance, and

(4) hypertriglyceridemia and/or low HDL cholesterolemia. Alternatively,the ninth aspect of the present invention provides a composition forpreventing occurrence of a cardiovascular event (primary prevention) ina hypercholesterolemia patient to be able to administered with HMG-CoARI, the composition containing at least EPA-E and/or DHA-E as itseffective component, wherein the patient also suffers from at least onerisk factor selected from the group consisting of

(1) obesity,

(2) hypertension or prehypertension,

(3) diabetes, prediabetes, or abnormal glucose tolerance, and

(4) hypertriglyceridemia and/or low HDL cholesterolemia.

While the EPA-E content in the total fatty acid and dosage are notparticularly limited as long as intended effects of the presentinvention are attained, the EPA-E used is preferably the one having ahigh purity, for example, the one having the proportion of the EPA-E inthe total fatty acid and derivatives thereof of preferably 40% by weightor higher, more preferably 90% by weight or higher, and still morepreferably 96.5% by weight or higher. The daily dose in terms of EPA-Eis typically 0.3 to 6 g/day, preferably 0.9 to 3.6 g/day, and still morepreferably 1.8 to 2.7 g/day. Another preferable daily dose is 0.3 to 2.7g/day, and 0.3 to 1.8 g/day. Another preferable fatty acid included isDHA-E. While the compositional ratio of EPA-E/DHA-E, content of EPA-Eand DHA-E (hereinafter referred to as (EPA-E+DHA-E)) in the total fattyacid, and dosage of (EPA-E+DHA-E) are not particularly limited as longas intended effects of the present invention are attained, thecomposition is preferably the one having a high purity of EPA-E andDHA-E, for example, the one having a proportion of the (EPA-E+DHA-E) inthe total fatty acid and derivatives thereof of preferably 40% by weightor higher, more preferably 80% by weight or higher, and still morepreferably 90% by weight or higher. The daily dose in terms ofEPA-E+DHA-F is typically 0.3 to 10 g/day, preferably 0.5 to 6 g/day, andstill more preferably 1 to 4 g/day. Another preferable daily dose is 0.3to 6 g/day, 0.3 to 4 g/day, and 0.3 to 1 g/day. The content of otherlong chain saturated fatty acids is preferably low, and among the longchain unsaturated fatty acids, the content of ω6 fatty acids, and inparticular, the content of arachidonic acid is preferably as low as lessthan 2% by weight, and more preferably less than 1% by weight.

The composition of the present invention contains EPA-E and/or DHA-E,and has the effect of preventing occurrence of cardiovascular events inhealthy people or those suffering from the risk factors ofhyperlipidemia, diabetes, and hypertension when the composition isorally administered, and in particular, of preventing occurrence ofcardiovascular events in hypercholesterolemia patients who have beentreated with HMG-CoA RI but still suffering from the risk of thecardiovascular events. The composition of the present invention may alsobe used in combination with the HMG-CoA RI, and such combination mayfurther prevent the occurrence of the cardiovascular events.

The composition of the present invention may be used with other drugs,for example, antiplatelet drugs such as aspirin, ticlopidine,clopidogrel, prasugrel, and cilostazol; anticoagulants such as warfarin,heparin, and ximelagatran; antihypertensive drugs such as angiotensin IIreceptor antagonists (candesartan, losartan, valsartan, etc.),angiotensin converting enzyme inhibitors, calcium channel antagonists(amlodipine, cilnidipine, etc.), and al blockers; diabetes drugs orabnormal glucose tolerance stimulants such as α-glucosidase inhibitors(voglibose, acarbose, etc.), biguanide drugs, thiazolidinedione drugs(pioglitazone, rosiglitazone, rivoglitazone, etc.), and prompt insulinrelease promoters (mitiglinide, nateglinide, etc.); antilipotropic drugsand antiarteriosclerotic drugs such as HMG-CoA RI as described above,fibrate drugs, squalene synthetase inhibitors (TAK-475, etc.), andcholesterol absorption inhibitors (ezetimibe, etc.), probucol, anionexchange resin, nicotinic acid drugs, phytostero, elastase, dextransulfate sodium sulfur, pantothenic acid, and polyenephosphatidylcholine.

The composition of the present invention contains smaller amounts ofimpurities such as saturated fatty acids and arachidonic acid which areunfavorable for cardiovascular events compared to fish oil or fish oilconcentrate, and accordingly, the intended effects can be attainedwithout causing problems like overnutrition or excessive intake ofvitamin A. In addition, since the effective component of the presentcomposition is in the form of an ester, the effective component is morestable to oxidation compared to the case of fish oil in which theeffective component is in the form of a triglyceride, and a sufficientlystable composition can be produced by adding a conventional antioxidant.In other words, it is the use of the EPA-E that has for the first timeenabled production of a composition for preventing onset ofcardiovascular events which can be used in clinical practice.

In the present invention, the term “icosapentaenoic acid” designatesall-cis-5,8,11,14,17-icosapentaenoic acid.

In the present invention, the term “hypercholesterolemia patient” meansthe patient with increased serum T-Cho concentration or serum LDL-Choconcentration. In a narrower sense, this term means the patientsuffering from hypercholesterolemia (serum T-Cho concentration of atleast about 220 mg/dl, and in more strict sense, at least 250 mg/dl) orhigh LDL cholesterolemia (serum LDL-Cho concentration of at least 140mg/dL).

In the present invention, the term “dyslipidemia” is the condition whichsatisfies at least one of high LDL cholesterolemia (i.e. fasting serumLDL cholesterol value of at least 140 mg/dL), low HDL cholesterolemia(i.e. fasting serum HDL cholesterol value of less than 40 mg/dL), andhypertriglyceridemia (i.e. fasting serum triglyceride value of at least150 mg/dL) according to the diagnostic criteria described in “Guidelinefor Preventing Arteriosclerotic diseases, 2007” (edited and published byJapan Atherosclerosis Society).

Of the risk factors treated in the present invention, “obesity” is thestate with excessive accumulation of fats in the body. For example,non-limiting examples of the obesity include a body mass index (BMI) ofat least 25, a waist measurement of at least 85 cm in male and at least90 cm in female. “Hypertension” is the state with an abnormal increasein resting arterial blood pressure of the greater circulatory system.For example, in the criteria proposed by Japanese Society ofHypertension at the time of the filing of this application, hypertensionis defined as a systolic blood pressure (SBP) of at least 140 mmHg or adiastolic blood pressure (DBP) of at least 90 mmHg. “Prehypertension” isthe condition with the blood pressure between the normal blood pressure(or optimal blood pressure) and the blood pressure in the hypertension,and this condition is also referred to as “mild elevated blood pressure”or “borderline hypertension”. Non-limiting exemplary criteria for suchcondition include a systolic blood pressure (SBP) of 120 to 139 mmHg ora diastolic blood pressure (DBP) of 80 to 89 mmHg. In the presentinvention, “hypertension or prehypertension” means a condition with asystolic blood pressure (SBP) of at least 120 mmHg or a diastolic bloodpressure (DBP) of at least 80 mmHg, more strictly, a systolic bloodpressure (SBP) of at least 135 mmHg or a diastolic blood pressure (DBP)of at least 85 mmHg, even more strictly a systolic blood pressure (SBP)of at least 140 mmHg or a diastolic blood pressure (DBP) of at least 90mmHg. “Diabetes” is the glucose metabolism disorder caused byhyposecretion of insulin from the insulin-producing cell (β cell) in thepancreas or insufficient action of the insulin in the target cell.Exemplary non-limiting criteria proposed by Japan Diabetes Society atthe time of the filing of this application is one of 1) fasting bloodglucose of at least 126 mg/dL, 2) 75 g glucose tolerance test at 2 hoursof at least 200 mg/dL, and 3) casual blood glucose level of at least 200mg/dL; or a hemoglobin A1c (HbA1c) of at least 6.5%. The criteria,however, are not limited to these. “Prediabetes” is the condition inwhich the blood glucose level is between the normal value and the valuein the diabetes. “Abnormal glucose tolerance” is the condition in whichthe blood glucose level in the glucose tolerance test is between thenormal value and the value in the diabetes. These conditions are alsoreferred to as the borderline diabetes, prediabetic state, and thediabetic high-risk group. For these conditions, exemplary non-limitingcriteria include a fasting blood glucose of 110 to 125 mg/dL, a 75 gglucose tolerance test at 2 hours of 140 to 199 mg/dL, and a hemoglobinA1c (HbA1c) of 5.6 to 6.4%. In the present invention, “diabetes,prediabetes, or abnormal glucose tolerance” means a condition with afasting blood glucose (FBS) of at least 110 mg/dL or a hemoglobin A1c(HbA1c) of at least 5.6%, more strictly, a fasting blood glucose (FBS)of at least 110 mg/dL or a hemoglobin A1c (HbA1c) of at least 5.9%, andeven more strictly with a fasting blood glucose (FBS) of at least 126mg/dL or a hemoglobin A1c (HbA1c) of at least 6.5%.“Hypertriglyceridemia” is the condition with an increased serumtriglyceride (TG) concentration, and strictly, with the serum TGconcentration of at least 150 mg/dL. “Low HDL cholesterolemia” is thecondition with a reduced serum HDL-C concentration, and strictly, withthe serum HDL-C concentration of less than 40 mg/dL. In the presentinvention, “hypertriqlyceridemia and/or low HDL cholesterolemia” meansthe state with a serum TG concentration of at least 150 mg/dL and/or aserum HDL-C concentration of less than 40 mg/dL. Thehypertriglyceridemia and the low HDL cholesterolemia are both diseasesincluded in the category of dyslipidemia, and they are mutuallyindependent risk factors. Combination of these risk factors, however, isknown to result in an increased risk of the occurrence of anarteriosclerotic disease. In the present invention, “thehypertriglyceridemia and/or the low HDL cholesterolemia” is treated as asingle risk factor.

In the present invention, the term “combined use of EPA-E with HMG-CoARI” include both the embodiment in which the EPA-E and the HMG-CoA RIare simultaneously administered and the embodiment in which both agentsare separately administered. When these agents are simultaneouslyadministered, they may be formulated either as a single combined drug orseparate drugs. When these agents are separately administered, EPA-E maybe administered either before or after the HMG-CoA RI. The doses andratio of the EPA-E and the HMG-CoA RI may be adequately selected.

In the present invention, the term “combined use of EPA-E and/or DHA-Ewith HMG-CoA RI” include both the embodiment in which the EPA-E and/orDHA-E and the HMG-CoA RI are simultaneously administered and theembodiment in which these agents are separately administered. When theseagents are simultaneously administered, they may be formulated either asa single combined drug or separate drugs. When these agents areseparately administered, EPA-E and/or DHA-E may be administered eitherbefore or after the HMG-CoA RI. The doses and ratio of the EPA-E and/orDHA-E and the HMG-CoA RI may be adequately selected.

The composition of the present invention has the action of preventingonset of the cardiovascular events by the sole administration of thecomposition, and in particular, the present composition is expected tohave the effect of preventing onset of the cardiovascular events whichcould not be prevented by the sole administration of the HMG-CoA RI. Inaddition, EPA-E has not only the action of reducing the serum T-Choconcentration and the serum TG, but also the action of suppressingplatelet aggregation based on inhibition of arachidonic acid cascade,which is a pharmacological action different from the HMG-CoA RI.Therefore, the action as described above can also be exerted by combinedadministration with the HMG-CoA RI.

Since EPA-E and DHA-F are highly unsaturated, inclusion of an effectiveamount of an antioxidant such as butylated hydroxytoluene, butylatedhydroxyanisole, propyl gallate, gallic acid, and pharmaceuticallyacceptable quinone, or α-tocopherol is preferable.

The preparation may be orally administered to the patient in the dosageform of tablet, capsule, microcapsule, granules, fine granules, powder,oral liquid preparation, syrup, or jelly. Preferably, the preparation isorally administered by filling in a capsule such as soft capsule ormicrocapsule.

The soft capsules containing high purity EPA-E (Epadel™ and Epadel S™)are commercially available in Japan as safe therapeutic agents forarteriosclerosis obliterans and hyperlipidemia with reduced sideeffects, and in such products, proportion of EPA-E in total fatty acidis at least 96.5% by weight. The soft capsule (Omacor™, Ross products,Reliant, and Pronova) containing about 46% by weight of EPA-E and about38% by weight of DHA-E is commercially available in the U.S., Europe,and other countries as a drug applied for hypertriglyceridemia. Thesedrugs may be purchased for use in the present invention.

The dose and administration period of the composition of the presentinvention for preventing the onset of the cardiovascular events is thedose and period sufficient for the expression of the intended action,and the dose and administration period may be adequately adjusteddepending on the dosage form, administration route, daily frequency,severity of the symptoms, body weight, age, and the like. When orallyadministered, the composition may be administered at a dose in terms ofEPA-E of 0.3 to 6 g/day, preferably 0.9 to 3.6 g/day, and morepreferably 1.8 to 2.7 g/day, and while such dose is typicallyadministered in 3 divided doses, if desired, such dose may beadministered in a single dose or in several divided doses. Thecomposition is preferably administered during or after the meal, andmore preferably, immediately (within 30 minutes) after the meal. Whensuch dose is orally administered, the administration period is typicallyat least 1 year, preferably at least 2 years, more preferably at least 3years and still more preferably at least 5 years. The administration,however, is preferably continued as long as there is a considerable riskof onset of the cardiovascular events. If necessary, drug holidays ofabout 1 day to 3 months, and preferably about 1 week to 1 month may begiven.

The HMG-CoA RI is preferably used according to the dosage regimenrecommended for the particular drug used, and the dose may be adequatelyadjusted depending on the type, dosage form, administration route, dailyfrequency, severity of the symptoms, body weight, gender, age, and thelike. When orally administered, the HMG-CoA RI is typically administeredat a dose of 0.05 to 200 mg/day, and preferably 0.1 to 100 mg/day in asingle dose or in two divided doses. If necessary, the total dose may beadministered in several divided doses. The dose of the HMG-CoA RI may bereduced depending on the dose of the EPA-E.

It is to be noted that pravastatin sodium (Mevalotin™ tablets and finegranules, Daiichi Sankyo Co., Ltd.), simvastatin (Lipovas™ tablets,Banyu Pharmaceutical Co., Ltd.), fluvastatin sodium (Lochol™ Tablets,Novartis Pharma K.K. and Tanabe Seiyaku Co., Ltd.), atorvastatin calciumhydrate (Lipitor™ tablets, Astellas Pharma Inc. and Pfizer Inc.),pitavastatin calcium (Livalo™, Kowa Company, Ltd. and Daiichi SankyoCo., Ltd.), and rosuvastatin calcium (Crestor™ tablets, AstraZeneca andShionogi & Co., Ltd.) are commercially available in Japan as drugs fortreating hyperlipidemia, and lovastatin (Mevacor™ tablets, Merck) iscommercially available in the U.S. as a drug for treatinghyperlipidemia. These drugs may be purchased and used according to theprescribed dosing schedules.

In the case of pravastatin sodium, the preferable daily dose is 5 to 60mg, and more preferably 10 to 20 mg, and in the case of simvastatin, thepreferable daily dose is 2.5 to 60 mg, and more preferably 5 to 20 mg.In the case of fluvastatin sodium, the preferable daily dose is 10 to180 mg, and more preferably 20 to 60 mg, and in the case of atorvastatincalcium hydrate, the preferable daily dose is 5 to 120 mg, and morepreferably 10 to 40 mg. In the case of pitavastatin calcium, thepreferable daily dose is 0.5 to 12 mg, and more preferably 1 to 4 mg,and in the case of rosuvastatin calcium, the preferable daily dose is1.25 to 60 mg, and more preferably 2.5 to 20 mg. In the case oflovastatin, the preferable daily dose is 5 to 160 mg, and morepreferably 10 to 80 mg, and in the case of cerivastatin sodium, thepreferable daily dose is 0.075 to 0.9 mg, and more preferably 0.15 to0.3 mg. The dose, however, is not limited to those as described above.

EXAMPLES

Next, the effects of the composition of the present invention aredemonstrated by referring to Examples, which by no means limit the scopeof the present invention.

Example 1 Effect of the EPA-F in Preventing Occurrence of CardiovascularEvents in Patients Having Multiple Risk Factors Trial Procedure

This trial corresponds to a partial analysis of the results obtained inJELIS (Japan EPA Lipid Intervention Study) which is a large scaleclinical trial of high purity EPA preparation which was presented in TheHeart Failure Society of America 2005 Annual Meeting (for generalinformation on JELIS, see Medical Tribune, issue of Nov. 17, 2005,Feature article 3, pp. 75-76).

More specifically, for the EPA-E group (7503 cases) and the controlgroup (7478 cases) evaluated for the primary prevention effect in the18,645 subject patients of the JELIS trial (EPA-E group (9,326 cases)and control group (9,319 cases)), occurrence of the cardiovascularevents was observed and analysed for 5 years from the start of theadministration in relation to the number of risk factors at theregistration as defined by the following (1) to (4):

(1) obesity: body mass index (BMI) of at least 25;

(2) hypertension or prehypertension: systolic blood pressure (SBP) of atleast 140 mmHg or diastolic blood pressure (DBP) of at least 90 mmHg;

(3) diabetes, prediabetes, or abnormal glucose tolerance: fasting bloodglucose (FBS) of at least 126 mg/dL or hemoglobin A1c (HbA1c) of atleast 6.5%;

(4) hypertriglyceridemia or low HDL cholesterolemia: a triglyceride (TG)of at least 150 mg/dL or a HDL-C of less than 40 mg/dL. The EPA-E groupwas orally administered with Epadel (Mochida Pharmaceutical Co., Ltd.)typically at an adult dose of 600 mg per administration and 3 times aday after the meal. However, in the case of abnormal serum TG, the dosecould be increased to 900 mg per administration and 3 times a day. Inboth groups, pravastatin sodium (Mevalotin™ tablets and fine granules,Daiichi Sankyo Co., Ltd.), simvastatin (Lipovas™ tablets, BanyuPharmaceutical Co., Ltd.), or atorvastatin calcium hydrate (Lipitor™tablets, Astellas Pharma Inc. and Pfizer Inc.) was used for the basedrug, and these drugs were orally administered according to theprescribed dosage regimen. More specifically, pravastatin sodium wasorally administered at a daily dose of 10 to 20 mg in a single dose ortwo divided doses; simvastatin was orally administered at a daily doseof 5 to 20 mg in a single dose; atorvastatin calcium hydrate was orallyadministered at a daily dose of 10 to 40 mg in a single dose.

Results

The number of occurrence of cardiovascular events in the observationperiod of 5 years, incidence (%), and rate of suppression of theincidence of the cardiovascular events in the EPA-E group with respectto the control group are shown in Table 1 for each number of riskfactors. The rate of suppression of the incidence of the cardiovascularevents was calculated by the formula: [{(incidence in the controlgroup)−(incidence in the EPA-E group)}/incidence in the controlgroup]×100.

[Table 1]

TABLE 1 Incidence in the Incidence in the control group EPA-E groupNumber of (cases of (cases of Rate of risk occurrence/ occurrence/suppression factors all cases, %) all cases, %) (%) 0 14/1309 11/1326 22(1.1) (0.8) 1 29/2424 25/2468 15 (1.2) (1.0) 2 46/2324 34/2238 23 (2.0)(1.5) 3 29/1205 28/1229 5 (2.4) (2.3) 4 9/216 6/242 40 (4.2) (2.5) 1-275/4748 59/4706 21 (1.6) (1.3) 1-3 104/5953  87/5935 18 (1.7) (1.5) 1-4113/6169  93/6177 18 (1.8) (1.5) 2-3 75/3529 62/3467 16 (2.1) (1.8) 2-484/3745 68/3709 18 (2.2) (1.8) 3-4 38/1421 34/1471 14 (2.7) (2.3)

The incidence (%) of cardiovascular events was found to increase withthe increase in the number of risk factors. While the incidence was 1.1%for the risk factor number of 0 and 4.2% for the risk factor number 4 inthe control group, the incidence was 0.8% in the risk factor number 0and 2.5% for the case of risk factor number 4 in the group administeredwith the EPA-E. As evident from Table 1, for all cases of both groupswith 1 to 4 risk factors, the cardiovascular event incidence was lowerin the group administered with the EPA-E compared to the control group,and the cardiovascular events were suppressed by 5 to 40%. The effect ofpreventing occurrence of the cardiovascular events by the administrationof the EPA-E was thereby confirmed for the hypercholesterolemia patientshaving the risk factors.

From the results of the trial as described above, the number ofoccurrence of cardiovascular events in the observation period of 5years, incidence (%), and rate of suppression of the incidence of thecardiovascular events in the EPA-E group with respect to the controlgroup were calculated for the male patients having at least two riskfactors. The results are shown in Table 2. (The calculation wasconducted by the same procedure as described above.)

[Table 2]

TABLE 2 Incidence in the Incidence in the control group EPA-E groupNumber of (cases of (cases of Rate of risk occurrence/ occurrence/suppression factors all cases, %) all cases, %) (%) 2-4 43/1053 19/106556 (4.1) (1.8)

FIG. 1 is a graph prepared by plotting the incidence of thecardiovascular events in Y-axis and time after the start of the trial inX-axis.

As evident from Table 2 and FIG. 1, in the case of male patients havingtwo or more risk factors, EPA-E significantly suppressed the occurrenceof cardiovascular events. It was also confirmed that decrease in theincidence of the cardiovascular events was significant after 2 years ormore from the start of the administration. At the end of the trial, therate of suppression of the cardiovascular event occurrence was 56%compared to the control group (the value after correcting the dispersionbetween groups was 55%; see FIG. 1).

From the results of the trial as described above, the number ofoccurrence of cardiovascular events in the observation period of 5years, incidence (%), and rate of suppression of the incidence of thecardiovascular events in the EPA-E group with respect to the controlgroup were calculated for the patients exhibiting a triglyceride (TG) ofat least 150 mg/dL and a HDL-C of less than 40 mg/dL as the riskfactors. The results are shown in Table 3. (The calculation wasconducted by the same procedure as described above.)

[Table 3]

TABLE 3 Incidence in the Incidence in the control group EPA-E group(cases of (cases of Rate of occurrence/ occurrence/ suppression Riskfactor all cases, %) all cases, %) (%) TG of at 21/475 11/482 48 least150 mg/dL (4.4) (2.3) and HDL-C of less than 40 mg/dL

FIG. 2 is a graph prepared by plotting the incidence of thecardiovascular events in Y-axis and time after the start of the trial inX-axis.

As evident from Table 3 and FIG. 2, EPA-E significantly suppressedoccurrence of cardiovascular events in the patients having the riskfactors of the triglyceride (TG) of at least 150 mg/dL and the HDL-C ofless than 40 mg/dL. It was also confirmed that decrease in the incidenceof the cardiovascular events was significant after 2 years or more fromthe start of the administration. At the end of the trial, the rate ofsuppression of the cardiovascular event occurrence was 48% compared tothe control group (the value after correcting the dispersion betweengroups was 53%; see FIG. 2). This suggests that the compositioncontaining EPA-E as its effective component effectively prevents theoccurrence of the cardiovascular event in the patient having the serumTG/HDL-C ratio of at least 3.75. It is also to be noted that, while theevents that occurred in the control group were fatal myocardialinfarction, nonfatal myocardial infarction, new occurrence of angina andcardiovascular angioplasty, the events that occurred in the EPA-E groupwere either nonfatal myocardial infarction or new occurrence of angina,and occurrence of fatal events was not found in the EPA-E group.

In addition, in the group of patients having the risk factor of thetriglyceride of at least 150 mg/dL, the occurrence of the cardiovascularevents was suppressed by 15% in the EPA-E group compared to the controlgroup; and in the group of patients having the risk factor of HDL-C ofless than 40 mg/dL, the occurrence of the cardiovascular events wassuppressed by 35% compared to the control group (both values areuncorrected values).

As described above, a significant effect of the EPA-E administration wasconfirmed for the prevention of the occurrence of the cardiovascularevents in the hypercholesterolemia patients having the risk factors.

1. A composition for preventing occurrence of a cardiovascular event ina hypercholesterolemia patient, the composition comprising ethylicosapentate as its effective component, wherein the patient alsosuffers from at least one risk factor selected from the group consistingof (1) obesity, (2) hypertension or prehypertension, (3) diabetes,prediabetes, or abnormal glucose tolerance, and (4) hypertriglyceridemiaand/or low HDL cholesterolemia.
 2. The composition according to claim 1,wherein the hypercholesterolemia patient is a patient also sufferingfrom two or more of the risk factors.
 3. The composition according toclaim 1, wherein the obesity is defined by a body mass index (BMI) of atleast 25; the hypertension or the prehypertension is defined by asystolic blood pressure (SBP) of at least 140 mmHg or a diastolic bloodpressure (DBP) of at least 90 mmHg; the diabetes, the prediabetes, orthe abnormal glucose tolerance is defined by a fasting blood glucose(FBS) of at least 126 mg/dL or a hemoglobin A1c (HbA1c) of at least6.5%; and the hypertriglyceridemia and/or the low HDL cholesterolemia isdefined by triglyceride (TG) of at least 150 mg/dL and/or a HDL-C ofless than 40 mg/dL.
 4. The composition according to claim 1, wherein thecontent of the ethyl icosapentate is at least 96.5% by weight inrelation to the total content of fatty acid and derivatives thereof. 5.The composition according to claim 1, wherein the ethyl icosapentate isorally administered at a dose of 1.8 g/day to 2.7 g/day.
 6. Thecomposition according to claim 1, wherein the composition is used incombination with a 3-hydroxy-3-methylglutaryl coenzyme A reductaseinhibitor.
 7. The composition according to claim 1, wherein thehypercholesterolemia patient is a male patient.
 8. The compositionaccording to claim 1, wherein the hypercholesterolemia patient is apatient also suffering from hypertriglyceridemia and low HDLcholesterolemia.